1. Field of the Invention
This invention relates to certain novel 2, 3, 6 substituted quinazolinone compounds which have demonstrated enhanced in vivo activity as angiotensin II (AII) antagonists and are therefore useful in alleviating angiotensin induced hypertension and for treating congestive heart failure.
2. Description of the Prior Art
The enzyme renin acts on a blood plasma .alpha..sub.2 -globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting enzyme to AII. The substance AII is a powerful vasopressor agent which is implicated as a causative agent for producing high blood pressure in mammals. Therefore, compounds which inhibit the action of the hormone angiotensin II (AII) are useful in alleviating angiotensin induced hypertension.
Furukawa et al., in U.S. Pat. No. 4,340,598, issued Jul. 20, 1982, discloses hypotensive and angiotensin II receptor blocking imidazole derivatives of the formula: ##STR2## wherein R.sup.1 is lower alkyl or phenyl C.sub.1-2 alkyl optionally substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl or phenyl optionally substituted; one of R.sup.3 and R.sup.4 is --(CH.sub.2).sub.n COR.sup.5 where R.sup.5 is amino, lower alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R.sup.3 and R.sup.4 is hydrogen or halogen; provided that R.sup.1 is lower alkyl or phenethyl when R.sup.3 is hydrogen, n=1 and R.sup.5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa et al., in European Patent Application No. 103,647 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension and have angiotensin II receptor blocking activity of the formula: ##STR3## where R represents lower alkyl and salts thereof.
D. J. Carini, et al. in published European Patent Applications No. 87109919.8, filed Sep. 7, 1987 and No. 89100144.8, filed May 1, 1989 disclose angiotensin II receptor blocking imidazoles of the formula: ##STR4## wherein the definitions of the substituents may be found within the applications.
P. Aldrich et al., in U.S. Pat. No. 4,874,867, issued Oct. 17, 1989, describes tetrazole intermediates of the formula: ##STR5## wherein X.sup.2 and X.sup.1 are defined therein. These intermediates are described as useful for producing compounds which are useful as inhibitors of the hormone angiotensin II (AII).
D. J. Carini et al., in U.S. Pat. No. 4,880,804, issued Nov. 14, 1989, described substituted benzimidazoles useful as inhibitors of the hormone angiotensin II (AII) of the formula: ##STR6## wherein R.sup.1 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3, or ##STR7## R.sup.2 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms; R.sup.3 is alkyl of 1 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms both of which may be optionally substituted with a halogen atom, --OR.sup.4 or up to two --CO.sub.2 R.sup.4 ; with the proviso that when R.sup.3 is methyl, it must be substituted with --OR.sup.4 or --CO.sub.2 R.sup.4 ; R.sup.4 is H, or alkyl of 1-4 carbon atoms; A is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen, alkoxy of 1 to 6 carbon atoms; ##STR8## B is H, alkyl of 1 to 10 carbon atoms, C.sub.r F.sub.2r+1 where r=1-6, C.sub.6 F.sub.5, halogen or alkoxy of 1 to 6 carbon atoms; X is a carbon-carbon single bond, --CO--, --O--, --NHCO--, or --OCH.sub.2 --.
D. J. Carini et al. in published European Patent Application No. 89100142.2, filed May 1, 1989, discloses angiotensin II receptor blocking pyrroles, pyrazoles and triazoles such as: ##STR9##
There has been no teaching or suggestion that the heretofore known antagonists of AII have the quinazolinone structure.